A tumor comprising abnormal cells is known to selectively absorb certain dyes perfused into the site to a much greater extent than surrounding tissue. For example, tumors of the pancreas and colon may absorb two to three times the volume of certain dyes, compared to normal cells, and intracranial gliomas show up to a 28 times level of absorption. Once pre-sensitized by dye tagging, the cancerous or abnormal cells can be destroyed by irradiation with light of an appropriate wavelength or waveband corresponding to an absorbing wavelength or waveband of the dye, with less damage to normal tissue. This procedure, which is known as photodynamic therapy (PDT), has been clinically used to treat metastatic breast cancer, bladder cancer, lung carcinomas, esophageal cancer, basal cell carcinoma, malignant melanoma, ocular tumors, head and neck cancers, and other types of malignant tumors. Because PDT may be selective in destroying abnormal cells that have absorbed more of the dye, it can successfully be used to kill malignant tissue with less effect on surrounding benign tissue in the brain and other critical areas.
Typically, invasive applications of PDT have been used during surgical procedures employed to gain access to a treatment site inside the body of the patient. Relatively high intensity light sources are used, to reduce the duration of the treatment, and thus the time required for the surgery, and because the majority of the prior art teaches that very high intensity light will more likely kill all of the malignant cells. Optical fibers in a hand-held probe are often used to deliver the intense light to the surgically exposed treatment site from a remote source, to reduce damage to surrounding tissue from the heat developed by the light source. High power lasers or solid state laser diode arrays in a remote light source coupled to the optical fibers are normally used for the light source. A typical prior art light source for PDT would provide from about 0.10 to more than 1.0 watts of optical power to achieve the high intensity, short duration exposures that are preferred. Because of the relatively high light intensity and power required to achieve it, apparatus to provide PDT is often too physically large and too heavy to be readily moved about with the patient.
The theoretical basis behind PDT is that the light energy absorbed by dye molecules in the malignant cells is transferred to dissolved oxygen to produce a reactive species called "singlet oxygen." This highly reactive form of oxygen kills cancer cells and damages tumor vasculature. Since the concentration of dissolved oxygen in cells is comparatively low, it is possible that after all available oxygen is activated and/or reacted with the cell materials, any additional increase in light intensity will have a negligible incremental effect on the tumor or in killing malignant cells. The limiting factor on the rate of malignant cell death in PDT may well be the rate at which additional oxygen diffuses into the treatment site from surrounding tissue and through replenishment via the vascular system. Contrary to the teachings of most of the prior art, the effectiveness of each photon of light impacting the treatment area may be highest at very low light intensities, over extended treatment times, and the optical efficiency may in fact decrease with increasing exposure level.
Several researchers, including Haas et. al., have shown that the level of cytotoxicity in photodynamic therapy appears to be proportional to the product of the integrated light exposure and the photoreactive agent's concentration, rather than to the instantaneous light intensity. In other words, the degree of PDT response is dominated by the total amount of light absorbed by the photoreactive agent over the treatment period. It can therefore be argued that if: (a) the photoreactive agent's concentration in the target tissue is maintained at a therapeutic level, and (b) apparatus for delivering light of the proper wavelength to a treatment site over an extended period is available, then the benefits of PDT can be realized with a less aggressive and potentially less costly treatment carried out over a period of days to weeks. Longer treatment periods at lower dosage rates may have other benefits as well, since high dose rates continued over extended periods can result in adverse normal tissue response.
Maintenance of therapeutic photoreactive agent levels is not difficult. It is well-known that many PDT photoreactive agents have a long half-life in the human body. In some cases, it is necessary for the patient to avoid direct sunlight for up to 30 days to avoid sunburn or phototoxic side effects.
It has been shown possible, in certain cases, to obtain improved therapeutic results in PDT at a low light level. As reported by J. A. Parrish in "Photobiologic Consideration in Photoradiation Therapy," pp. 91-108, Porphyrin Photosensitization, Plenum Press, (1983), preliminary laboratory studies with hematoporphyrin and visible light suggest that the reciprocity effect does not always hold, and that low light intensity may be more effective in PDT, in an absolute sense. In these experiments, subcutaneous tumors in the flanks of newborn rats were treated with the same external dose of 620 nm radiation at intensities of 7.5, 28, and 75 mW/cm.sup.2. At the same total light dosage, Parrish found that greater tumor necrosis occurred at the lowest light intensity used.
In addition, several researchers have shown that combinations of certain photoreactive agents and low light levels exhibit very potent cytotoxicity. For example, Nitzan et. al. have shown that more than 99% of gram-positive Staphylococcus aureus and Streptococcus faecalis bacterial cultures can be killed with the application of 5 mW/cm.sup.2 of broad band light from a tungsten bulb for 30 minutes, if the cultures are initially dosed with 1-10 micrograms/ml of deuteroporphyrin. Continued application of light for 10-11 hours results in a sterile condition in the culture, i.e., no bacteria remain alive.
Labrousse and Satre have demonstrated a :similar photodynamic extermination of amoebae when dosed with low concentrations of 4'5'-Diiodofluorescein isothiocyanate dextran and irradiated for about 30 minutes with broad band light of 8-10 mW/cm.sup.2 from a tungsten lamp. Both of these experimental results are particularly significant because the fraction of a tungsten lamp's output energy that can be absorbed by either photoreactive agent is small, since each agent has a narrow absorbance waveband.
For all PDT light sources, the vast majority of the optical power delivered to tissue eventually degrades to heat. From a therapy perspective, it is likely that this heat load will augment the treatment due to improved chemical reaction rates at higher tissue temperatures. It is also true that cells kept above approximately 43.degree. C. are not viable. This effect is, in fact, used in the treatment of cancer using hyperthermia. In that situation, an attempt is made to heat the target tumor with radio frequency energy to a temperature on the order of 43.degree.-45.degree. C., while maintaining surrounding healthy tissue below 43.degree. C. Combining hyperthermia with conventional transcutaneous PDT has been shown by B. Henderson et al. to increase the efficacy of both treatments (see "Interaction of Photodynamic Therapy and Hyperthermia: Tumor Response and Cell Survival after Treatment of Mice in Vivo," Cancer Research, Vol. 45, 6071 (December 1985)). Combining hyperthermia treatment with PDT delivered, for example, by an implantable probe in accordance with the present invention, will very likely augment the effects of either treatment used alone in destroying tumors.
A wide range of therapeutic benefits may be realized with the apparatus and methods of the present invention, beyond destroying tumors. These benefits include, but are not limited to, the destruction of other abnormal cell types, the destruction of normal tissue for therapeutic ends, selective destruction of pathogenic microorganiisms, viruses, and other self-replicating disease agents, treatment of vascular or hematologic disorders, reducing or controlling inflammation, and the enhancement of normal cellular function, such as wound healing or immunologic response. It is contemplated that the PDT apparatus and methods disclosed below can be applied to providing such therapeutic benefits in both plants and animals.
Development of a method and apparatus for delivering light with an implantable probe, for extended periods of time, well beyond that available during the time that a patient's subdermal system is exposed during surgery, is therefore desirable. The prior art does not teach the benefits of the long term exposure using light provided by an implanted light source and therefore does not disclose an appropriate method or apparatus for administering such treatment. The benefits and advantages of this procedure and of the apparatus disclosed herein that was developed to effect the technique will become evident from the following Description of the Preferred Embodiments and the attached drawings.